威罗菲尼
黑色素瘤
细胞毒性
生物信息学
细胞生长
下调和上调
癌症研究
作用机理
生物
细胞凋亡
化学
体外
生物化学
基因
转移性黑色素瘤
作者
Haiyan Wang,Pian Yu,Xi-Sha Chen,Hui Wei,Shi-Jie Cao,Rui Zhang,Yi Zhang,Yongguang Tao,Dong-Sheng Cao,Feng Qiu,Yan Cheng
出处
期刊:Acta Pharmacologica Sinica
日期:2021-09-29
卷期号:43 (6): 1594-1604
被引量:2
标识
DOI:10.1038/s41401-021-00745-x
摘要
Abstract Physapubenolide (PB), a withanolide-type compound extracted from the traditional herb Physalis minima L., has been demonstrated to exert remarkable cytotoxicity against cancer cells; however, its molecular mechanisms are still unclear. In this study, we demonstrated that PB inhibited cell proliferation and migration in melanoma cells by inducing cell apoptosis. The anticancer activity of PB was further verified in a melanoma xenograft model. To explore the mechanism underlying the anticancer effects of PB, we carried out an in silico target prediction study, which combined three approaches (chemical similarity searching, quantitative structure-activity relationship (QSAR), and molecular docking) to identify the targets of PB, and found that PB likely targets 3-hydroxy-methylglutaryl CoA reductase (HMGCR), the rate-limiting enzyme of the mevalonate pathway, which promotes cancer cell proliferation, migration, and metastasis. We further demonstrated that PB interacted with HMGCR, decreased its protein expression and inhibited the HMGCR/YAP pathway in melanoma cells. In addition, we found that PB could restore vemurafenib sensitivity in vemurafenib-resistant A-375 cells, which was correlated with the downregulation of HMGCR. In conclusion, we demonstrate that PB elicits anticancer action and enhances sensitivity to vemurafenib by targeting HMGCR.
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